It is believed that chronic hyperglycemia decreases insulin secretion and lowers insulin sensitivity, further causing increases in blood glucose levels and aggravating diabetes. Hyperglycemia is considered to be a major risk factor for complications of diabetes. Thus, maintaining blood sugar at a normal level seems to improve insulin sensitivity and suppress the onset of complications of diabetes. Biguanides, sulfonylureas, glycosidase inhibitors, and insulin sensitizing agents have so far been used as therapies of diabetes. However, adverse reactions or side effects have been reported, such as lactic acidosis for the biguanides, hypoglycemia for the sulfonylureas, and diarrhea and serious hepatic function disorder for the glycosidase inhibitors. Hence, drugs for treatment of diabetes, which have new mechanisms of action different from those of the conventional drugs, are desired to be developed.
Phlorizin, which is a glucose derivative isolated from natural products, was shown to inhibit the reabsorption of excess glucose in the kidney and promote the excretion of glucose, exhibiting an antihyperglycemic action (non-patent documents 1 and 2). Then, this reabsorption of glucose was shown to be ascribed to sodium-dependent glucose cotransporter 2 (SGLT2) present at the S1 site of the renal proximal tubule (non-patent document 3). Since the administration of phlorizin, a specific SGLT inhibitor, to rats with diabetes was demonstrated to promote glucose excretion to urine and produce an antihyperglycemic action, SGLT2-specific inhibitors have been regarded as new target molecules for therapies of diabetes.
Against such a background, numerous phlorizin-related compounds have been studied, and O-aryl glucosides have been disclosed (patent documents 1 to 11). However, when orally administered, O-aryl glucosides have their glycoside linkage hydrolyzed with β-glycosidase present in the small intestine, and in the unchanged form, are poor in absorption efficiency. Thus, their prodrugs are under development.
A report has been issued of compounds which are O-aryl glucosides converted into chemically stable C-aryl glycosides (patent document 12). Compounds having the glucose portion directly bound to aryl or heteroaryl, as described above, have also been reported (patent documents 13 to 15). However, C-aryl glycosides, which are the compounds disclosed in these documents (patent documents 12 to 15), are amorphous substances in many cases, and thus their pharmaceutical manufacturing is problematical (patent document 12). For this reason, these compounds needed to be crystallized together with suitable amino acids such as phenylalanine and proline (U.S. Pat. No. 6,774,112). Accordingly, compounds, which have excellent crystallinity, whose purification, storage and pharmaceutical manufacturing are easy, and which are easy to handle as drugs, were required.
There have been reports of methods for producing aryl 5-thio-β-D-glucopyranoside (O-aryl 5-thio-β-D-glucoside) or heteroaryl 5-thio-β-D-glucopyranoside (O-heteroaryl 5-thio-β-D-glucoside) derivatives having 5-thioglucose and aryl or heteroaryl bound via β-glucoside (patent documents 16 to 17). The SGLT-inhibiting action of these compounds is also reported (patent documents 18 to 19). As seen in the report (patent document 16), however, glycosylation completely differs in the behavior of the reaction according to the type of sugar, and the reaction conditions permitting glycosylation from glucose cannot be applied to thioglucose.
Thus, there have been no methods for producing 1-thio-D-glucitol derivatives having 5-thioglucose and an aryl or hetero ring directly bound, and there have been no reports of 1-thio-D-glucitol derivatives. Some of the compounds shown in patent documents 1 to 15 have already been subjected to clinical trials, and there is a possibility that new drugs for treatment of diabetes will be commercially available in the future. However, during clinical trials in humans, their development may become difficult for some reason, and thus a group of compounds having the same mechanism of action, but having a hitherto inexistent new skeleton are needed.    Non-patent document 1: Rossetti, L., et al. J. Clin. Invest., Vol. 80, 1037, 1987    Non-patent document 2: Rossetti, L., et al. J. Clin. Invest., Vol. 79, 1510, 1987    Non-patent document 3: Kanai, Y., et al. J. Clin. Invest., Vol. 93, 397, 1994    Patent document 1: European Patent Application Publication No. 0850948    Patent document 2: European Patent Application Publication No. 0598359    Patent document 3: International Publication No. WO01/068660 pamphlet    Patent document 4: International Publication No. WO01/016147 pamphlet    Patent document 5: International Publication No. WO01/074834 pamphlet    Patent document 6: International Publication No. WO01/074835 pamphlet    Patent document 7: International Publication No. WO02/053573 pamphlet    Patent document 8: International Publication No. WO02/068439 pamphlet    Patent document 9: International Publication No. WO02/068440 pamphlet    Patent document 10: International Publication No. WO02/036602 pamphlet    Patent document 11: International Publication No. WO02/088157 pamphlet    Patent document 12: International Publication No. WO01/027128 pamphlet    Patent document 13: US Patent Application Publication No. 2001/0041674    Patent document 14: International Publication No. WO04/013118 pamphlet    Patent document 15: International Publication No. WO04/080990 pamphlet    Patent document 16: International Publication No. WO04/014930 pamphlet    Patent document 17: International Publication No. WO04/089966 pamphlet    Patent document 18: International Publication No. WO04/014931 pamphlet    Patent document 19: International Publication No. WO04/089967 pamphlet